Implantable drug delivery system with piston actuation

ABSTRACT

An implantable drug delivery system includes a housing having a base end and a discharge end, for holding drug solution at the discharge end, a valve disposed at the discharge end to allow a drug solution to flow from inside the housing, through the valve and out of the housing when solution pressure is applied to the valve, a piston slidably disposed in the housing to slide between the base end and discharge end to force solution toward the discharge end and out the valve, and a spring disposed in the housing between the piston and the base end thereof for urging the piston toward the discharge end. A plurality of different length tethers are connected at one end to the piston and at the other end to a respective release node located at the base end of the housing. Each release node holds the other end of a respective one of the tethers until a release signal is received at which time it releases the tether. A timing circuit is disposed in the housing at the base end to supply release signals sequentially to the nodes in order of the shortest tether node to the longest tether node so that as a tether is released, the piston is allowed to move toward the discharge end of the housing to thereby discharge or bolus of drug solution from the housing, until the next shortest unreleased tether stops further movement of the piston.

BACKGROUND OF THE INVENTION

The present invention relates to simple and efficient piston-actuateddrug delivery systems for implantation into an animal or human fordelivery of drug to the animal or human incrementally over some periodof time.

It is well known in the fields of animal husbandry and veterinarymedicine that it is desirable and in some instances necessary to treator care for farm animals by periodically injecting the animals (oradministering orally) with various drugs. If a series of injections orother administrations are required, this may require finding androunding up the animals, administering the desired drug (or differentdrugs), and then releasing the animals until the next drugadministration is due. Of course, it can be time consuming and costly,each time treatment of a farm animal is required, to locate the farmanimal and bring it to a suitable location for treatment. It has beenproposed that drug delivery devices be implanted in farm animals for theperiodic release of drugs, examples of such devices being disclosed inU.S. Pat. Nos. 4,564,363, 4,326,522, 4,425,117, 4,439,197, 3,840,009,4,312,347 and 4,457,752.

Although the devices disclosed in the above-cited patents serve todeliver a drug or solution to the body of an animal or person in whichthey are located, the devices are typically limited to specificapplications, allow for a one-time discharge (a continuous delivery) ofdrug into the system of the body in which the device is located, arebulky and therefore difficult to place and maintain in the body, or arecomplicated and costly to manufacture and use.

SUMMARY OF THE INVENTION

It is an object of the invention to provide a simple and efficient drugdelivery system which may be implanted in the body of an animal or humanfor timed, periodic release of the drug into the body.

It is also an object of the invention to provide such a drug deliverysystem which is compact and can be readily manufactured.

It is a further object of the invention to provide such a drug deliverysystem which has a high ratio of drug volume to housing or packagevolume.

It is an additional object of the invention to provide such a drugdelivery system which is reliable and substantially leak free.

The above and other objects of the invention are realized in a specificillustrative embodiment of an implantable drug delivery system whichincludes a housing having a base end and a discharge end, for holdingdrug formulation at the discharge end, a one-way valve disposed at thedischarge end to allow formulation to flow or move through the valve andout of the housing when formulation pressure is applied to the valve, apiston slidably disposed in the housing to slide between the base endand discharge end to force formulation toward the discharge end and outthe valve, and a biasing element for urging the piston toward thedischarge end of the housing. Also included is a restraining member forallowing successive step-wise movement of the piston toward thedischarge end of the housing in response to release signals, but forotherwise restraining movement of the piston. A control unit located atthe base end of the housing supplies release signals to the restrainingmember in a predetermined sequence so that drug formulation issuccessively forced out of the housing in discreet amounts.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features and advantages of the inventionwill become apparent from a consideration of the following detaileddescription presented in connection with the accompanying drawings inwhich:

FIG. 1 is a perspective view of an implantable drug deliverymultiple-vesicle device made in accordance with the principles of thepresent invention;

FIG. 2 is a side, fragmented, cross-sectional view of the device of FIG.1;

FIG. 3 is a top, plan, cross-sectional view of another embodiment of amultiple-vesicle drug delivery system made in accordance with theprinciples of the present invention;

FIG. 4 is a side view of the embodiment of FIG. 3 but showing only a fewof the component parts;

FIG. 5 is an isometric, exploded, partially cutaway view of stillanother embodiment of a drug delivery system made in accordance with theprinciples of the present invention and utilizing piston or plungerdischarge elements in multiple vesicles;

FIG. 6 is a side, cross-sectional view of still another embodiment of adrug delivery system made in accordance with the principles of thepresent invention and utilizing a plunger in a single cylindricalvesicle;

FIG. 7 is a top, plan view of the release mechanism of FIG. 6;

FIG. 8 is a fragmented, side, cross-sectional view of another embodimentof a drug delivery system made in accordance with the principles of thepresent invention;

FIG. 9 is a side, elevational view of one embodiment of a pyrotechnicgas generating element made in accordance with the present invention;

FIG. 10 is a top plan view of the embodiment of FIG. 9;

FIG. 11 is a side, elevational view of another embodiment of apyrotechnic gas generating element made in accordance with the presentinvention; and

FIG. 12 is a top plan view of the embodiment of FIG. 11.

DETAILED DESCRIPTION

Referring to FIGS. 1 and 2 of the drawings, there is shown a lowprofile, compact drug delivery system made in accordance with thepresent invention to include a housing 4 having formed therein two (ormore) rows of vesicles or compartments 8, each having top, polygonallyshaped cross-sections to allow compact nesting together of thecompartments. The compartments shown in the FIGS. 1 and 2 embodimenthave triangular top cross sections, but other shapes could also be usedto achieve the desired nesting.

Positioned at one end of the two rows of compartments 8 is a utilitycompartment 12 in which is housed a battery 16, an oscillator 20, atiming circuit 24, and a receiver and antenna 26. The elements 16, 20,24 and 26 are mounted on a substrate 28 which forms the floor of theutility compartment 12 and the other compartments 8.

Each compartment 8 has an opening at the top which is covered by arupturable cover, such as the one cover 32 shown. The covers 32 mightillustratively be made of a thin metal foil or might be made of a thinplastic sheet. Score lines 36 may be formed in the cover 32 to morereadily facilitate the rupture of the cover and the release of thecontents of the corresponding compartment (to be discussed momentarily).The housing 4 might advantageously be made of injection moldedpolycarbonate or other plastics. The substrate 28 might illustrativelybe made of conventional circuit board material such as a fiberglass andepoxy composite or polyamide film, for carrying the circuit component16, 20, 24 and 26 and electrical conductors to be discussed later.

Disposed in each compartment 8 is a corresponding drug containment sack40 having a mouth 44 which circumscribes an opening 48 to the interiorof the sack (see FIG. 2). The mouth 44 of each drug containment sack isattached to the opening of the corresponding compartment, at the topthereof, to seal the inside of each sack from the inside of thecorresponding compartment. The drug containment sacks are provided forholding drug solution (or powder or granular formulation) to bedelivered to an animal into which the drug delivery system is implanted.The sacks 40 might illustratively be made of polyvinylidene chloride,fluorinated ethylene-propylene, or other suitably flexible and fluid andchemical impervious material.

Disposed at the bottom of each compartment on the substrate 28 is apyrotechnic gas generating element, typically a bead of material 52which is responsive to heat resulting from an electrical signal appliedto a heating element, thereby igniting and producing gas for filling thecorresponding compartment. Alternatively, a non-toxic foam may beproduced by an ignition material to similarly fill a correspondingcompartment. As a compartment fills with gas, the gas forces thecorresponding drug containment sack upwardly and the sack, in turn,forces drug solution against a corresponding cover 32 to rupture thecover and allow the drug solution and sack to be emitted from thecompartment. Sack 40b of FIG. 2 is shown fully pushed out of thecompartment 8b which ensures that all drug solution initially containedin the sack is released into the animal.

The pyrotechnic gas generating material 52 might illustratively be acomposition of nitrocellulose or polyvinyl nitrate. Although not shown,a second pyrotechnic gas generating bead might also be included in eachcompartment to be activated after the first bead has been activated tothereby better ensure the complete release of drug solution from eachcompartment.

The timing circuit 24 operates in response to a remotely transmittedsignal (transmitted by a transmitter 58) received by the receiver andantenna 26 to selectively and sequentially connect the battery 16 by wayof electrical conductors 56 to the pyrotechnic gas generating beads 52.Remotely transmitted signals could be used simply to initiate operationof the timing circuit 24 which would then periodically activate selectedgas generating beads 52 on its own, or the transmitted signals could beused to directly activate a bead with each transmitted signal. (Althoughthe conductors 56 are shown as being under the substrate 28 in FIG. 2,this is for illustrative purposes only and it should be understood thatthe conductors would be formed upon the substrate by conventionalphoto-lithographic, vacuum deposition, or other conventional conductorforming techniques.) The conductors 56 could illustratively be made of arelatively low resistance conductive ink made, for example, of a resinand carbon and silver particles. An alternative to initiating operationof the timing circuit 24 by radio or other signal transmission would besimply to internally set the timing circuit to begin operation somepredetermined time in the future--e.g., after supplying the drugdelivery system to an animal.

The oscillator 20 supplies an oscillatory signal to the timing circuit24 which is adapted to selectively connect the battery 16 to thepyrotechnic gas generating beads 52 in some preferred order (to activatethe beads) and with a predetermined delay between activation of thedifferent beads, to thereby discharge boluses of drug solution into theanimal over a period of time.

FIGS. 3 and 4 show another embodiment of a drug delivery system having ashort, cylindrically-shaped housing 104 having a plurality ofcompartments 108 formed in a circle about a central utility compartment112. The utility compartment 112 again includes a battery 116, anoscillator 120 and a timing circuit 124, all mounted on a substrate 128which forms a common floor for the utility compartment 112 and the othercompartments 108. (A receiver and antenna could also be provided forthis embodiment as well as the other embodiments, for remote operation,as explained for the FIGS. 1 and 2 embodiment.)

Although the compartments 108 could have openings at the top of thehousing 104, similar to the embodiment of FIGS. 1 and 2, thecompartments are shown as having openings 132 in the circumferentialouter wall of the housing. Drug containment sacks 136 are disposed ineach compartment for holding a drug solution, and rupturable covers 140are disposed over the compartment openings as best seen in FIG. 3.Alternatively to placing individual covers 140 over each of thecompartment openings, a single strip cover could be disposed at thecircumferential outer side of the housing 104 to cover all of theopenings, with appropriate scoring of the cover being made to allowrelease of drug solution only from those compartments which areactivated. A pair of individually activatable pyrotechnic gas generatingbeads 144 and 148 (FIG. 3) are disposed in each compartment on the wallopposite the compartment opening (or on the substrate floor), forproducing gas to discharge the contents of the compartment in responseto an electrical ignition signal.

FIG. 5 shows an isometric, exploded, partially cutaway view of a drugdelivery system having an elongate, tubular housing 204. Formed in thehousing is a central compartment or vesicle 208, and a plurality ofother vesicles 212 disposed in a circle about the central vesicle asshown. The vesicles extend along a substantial length of the housing 204generally in parallel with one another and include openings at the upperend of the housing. A rupturable cover 216 is disposed over the upperend of the housing to cover the openings of the vesicles, but to alsorupture and allow discharge of the contents of a vesicle when a certainfluid pressure is supplied to the cover from inside the vesicle.Although the vesicles 212 are shown to be generally the same size,different size vesicles could be provided to allow for delivery ofdifferent amounts of drug--both of this embodiment and the others.

The housing 204 also includes a bottom compartment 220 in which aredisposed a battery 224, an oscillator 228 and a timing circuit 232. Thecompartment 220 is separated from the vesicles 208 and 212 by a floor orsubstrate 236 in which are located a plurality of pyrotechnic gasgenerating beads 240. The circuit components 224, 228 and 232selectively and successively ignite the pyrotechnic gas generating beads240 in the same manner as discussed for the embodiments of FIGS. 1 and 2and FIGS. 3 and 4.

Disposed in each vesicle 208 and 212 near the bottoms thereof arepistons or plungers 244. The side surfaces of the plungers 244 areshaped to conform to and snugly fit within the side walls of thecorresponding vesicles so that as a plunger is forced upwardly in avesicle by gas pressure, it pushes out of the housing a drug formulationcontained in the vesicle. The plungers 244 are forced upwardly in thecorresponding vesicles by the activation of the pyrotechnic gasgenerating beads (or other geometric shapes) 240.

Advantageously, the plungers 244 are made of polyurethane, syntheticrubber or paraffin which will allow for a slidably tight fit within thevesicles and will also provide some lubrication to facilitate thesliding of the plungers. The housing 204 could illustratively be made ofinjection molded polycarbonate.

FIGS. 6 and 7 show respectively a side, cross-sectional view of anotherembodiment of an implantable drug delivery system, and a top plan viewof the release mechanism of the system. The FIGS. 6 and 7 system includea housing 304 having a base end 308 and a discharge end 312. A passiveone-way valve 316 is disposed in the discharge end of the housing toallow release of drug formulation contained in the housing when acertain fluid pressure is applied from inside the housing to the valve.

Disposed in the housing is a piston or plunger 320 having a springreceiving hollow 324 on the underneath side thereof. The exterior sidewall of the plunger 320 includes axially spaced apart wipers or seals328 and 332 for making intimate but slidable contact with the interiorside wall of the housing 304. The plunger 320 is positioned in thehousing 304 initially at a location to define a cavity or reservoir 336above the plunger for holding a drug formulation.

Also disposed in the housing 304 is a coil spring 340 which extends froma bottom wall at the base end of the housing 308 upwardly into thehollow 324 of the plunger 320. A battery 344, oscillator 348 and timingcircuit 352 are disposed within the coil spring 340 on the bottom wallof the housing (but could also be disposed in the plunger 320). Disposedabove the circuit elements 344, 348 and 352 is a release circuit card356 (a bottom view being shown in FIG. 7 with the oscillator 348 andtiming circuit 352 mounted thereon).

A plurality of different length tethers or fibers 360 are attached atone end to the underside of the plunger 320 and at the other end torelease nodes 364 disposed on the circuit card 356. The tethers 360serve to hold the plunger in place and prevent it from being movedupwardly toward the discharge end of the housing by the spring 340 untilselected tethers are released from the circuit cards. In particular,each of the tethers, being a different length, serve to hold or retainthe plunger 320 at different distances away from the circuit card 356until the tether holding the plunger at a respective length is releasedfrom its corresponding release node 364. In this manner, the tethers 360can be successively released to allow a stepwise movement upwardly ofthe plunger 320 to successively discharge boluses of drug formulationcontained in the reservoir 336.

The release nodes 364 are composed of a material (e.g.,ultra-high-modulus polyethylene) capable of holding the ends of therespective tethers 360 until the material is activated or ignited inresponse to an electrical signal to either sever or release thecorresponding tether end. Each release node 364 is coupled to the timingcircuit 352 which selectively supplies an electrical release signal fromthe battery 344 to the nodes. Release signals are supplied to therelease nodes 364 in the order of increasing tether length so that theshortest tether is first released to allow the plunger 320 to moveupwardly one increment, the next shortest tether is then released, etc.until the plunger has been forced by the spring 340 to the top of thehousing 304 at the discharge end.

In the event that any tether 360 is not released, then any subsequentrelease node 364 activated by the timing circuit 352 will not be able toallow any further movement of the plunger 320. Nevertheless, acompletion release node 366, located at the point of connection of thetethers 360 to the plunger 320, may be activated to sever or release alltethers to allow a final thrust of the plunger 320 toward the dischargeend 312 of the housing. In this manner, even though one of the tethers360 may have failed to release, activation of the release node 366 wouldprovide for the release of all the tethers and a final movement of theplunger 320.

FIG. 8 shows a fragmented, side, cross-sectional view of anotherembodiment of a drug delivery system which also utilizes a plunger 404slidably disposed in a housing 408. A coil spring, not shown but similarto the spring 340 of the system of FIG. 6, is also disposed in thehousing 408 to bias or urge the plunger 404 upwardly toward a dischargeend of the housing.

The plunger 404 is prevented from its upward movement by a single tether412 coupled at one end to the plunger 404 and at the other end to acircuit card 416. Successive pairs of points along the length of thetether 412 are joined together by release elements 420 to thus form aseries of loops 424 in the tether. The release elements join the twocorresponding points of the tether 412 together until activated byrelease signals supplied by way of conductors 428 by a circuit pack 432.As a release element 420 is activated, the two adjacent points of thetether 412 joined together are released so that the effective length ofthe tether increases to allow an upward movement of the plunger 404. Asa next release element is activated, another loop of the tether isreleased so that the tether again increases its effective length toallow another upward movement of the plunger 404. In this manner, bysuccessive application of release signals to the release elements 420,the plunger 404 is allowed successive upward movements to thereby forcedrug solution located above the plunger to discharge out the dischargeend of the housing 408.

FIGS. 9 and 10 show a side, elevational, partially cross-sectional viewand a top plan view respectively of a pyrotechnic gas generating elementsuitable for use in the embodiments of FIGS. 1 through 5 of thedrawings. The element is disposed on a substrate or base 504 to includea pyrotechnic material 508 which ignites easily and burns in response toan electrical signal supplied over lead 512 to an igniter strip 516.Such pyrotechnic material might advantageously be composed ofnitrocellulose, barium styphnate or tetrazene. The igniter strip 516might illustratively be made of nickel chromium. Lead 512 mightillustratively be copper, copper alloy or gold. The burning of thepyrotechnic material produces gas as required for forcing drugformulation from vesicles of drug delivery apparatus.

To actuate the gas generating element of FIGS. 9 and 10, an electricalsignal is supplied to the conductor 512 to flow through the igniterstrip 516 causing it to heat and combust the pyrotechnic material 508.

FIGS. 11 and 12 show a side, elevational view and top plan view ofanother pyrotechnic gas generating element which may be used in the drugdelivery apparatus of FIGS. 1-5. The element is disposed on a substrate604 which includes an electrical conductor 608 formed of aluminum.Disposed on the aluminum strip 608 is a strip of a composition 612 ofpalladium (about 95 percent) and ruthenium (about 5 percent) which isnarrowed or pinched at 616. Disposed over and about the composition 612is a mass of pyrotechnic material 620 as discussed earlier.

When an electrical signal is supplied to the conductor 608 and to thecomposition 612, the composition alloys--heats exothermally--and thisreaction progresses under the pyrotechnic material to ignite it and thusproduce the desired gas. The narrowed portion 616 presents greaterresistance to the electrical signal to start the alloying process.

In the manner described, simple, compact drug delivery units may beprovided for implantation into an animal to release successive, timedbursts of drug solution. The volume of each unit utilized for drugcontainment is high relative to the volumes used for containingcircuitry or other elements of the units.

It is to be understood that the above-described arrangements are onlyillustrative of the application of the principles of the presentinvention. Numerous modifications and alternative arrangements may bedevised by those skilled in the art without departing from the spiritand scope of the present invention and the appended claims are intendedto cover such modifications and arrangements.

What is claimed:
 1. An implantable drug delivery system comprisinganelongate housing having a plurality of elongate, generally parallelvesicles formed therein, said vesicles having an opening at one end anda bottom wall at the other end, a plurality of plungers, each disposedin a different one of the vesicles and shaped to fit and slide snugly inthe corresponding vesicle, said plungers initially positioned near thebottom walls of the vesicles to allow reception and holding of drugformulation in the vesicles above the plungers, a plurality of caps,each removably positioned over a respective opening of a vesicle toprevent release of drug formulation from the vesicles, said caps beingreleasable to release drug formulation when formulation is forcedagainst the caps by the upward movement of the plungers, a plurality ofgas generating means, each disposed at the bottom wall of a differentone of the vesicles and each being responsive to an ignition signal forigniting to generate gas and force a corresponding plunger upwardly topush drug formulation against a corresponding cap and out the vesicle,and means for selectively supplying ignition signals to said gasgenerating means.
 2. A system as in claim 1 wherein said ignition signalsupplying means is disposed in the housing below the bottom walls of thevesicles.
 3. A system as in claim 2 wherein one of said vesicles ispositioned centrally with the other vesicles positionedcircumferentially about the one vesicle.
 4. A system as in claim 2wherein said plungers are composed of material selected from the groupconsisting of polyurethane, synthetic rubber, and paraffin.
 5. A systemas in claim 2 wherein said caps are made of thin metallic foil.
 6. Asystem as in claim 2 wherein said caps are made of a polymeric sheet. 7.A system as in claim 2 wherein said housing comprises an integral,unitary structure.
 8. A system as in claim 6 wherein said housing isconstructed of injection molded polycarbonate.
 9. A system as in claim 2wherein each of said gas generating means comprises a pyrotechniccomposition of a gas generating material responsive to heat for furtherheating and producing gas, a heating element disposed in contact withthe composition for heating in response to an electrical signal, andwherein said ignition signals comprise electrical signals.
 10. A systemas in claim 9 wherein said heating element comprises a strip of nickelchromium, and wherein said composition is disposed over the strip.
 11. Asystem as in claim 9 wherein said heating element comprises acomposition of palladium and rethenium disposed in contact withaluminum.
 12. A system as in claim 9 wherein said ignition signalsupplying means comprisesa power source, and a switching circuit foroperating to selectively temporarily couple the power source to theheating elements in a predetermined sequence.
 13. A system as in claim12 wherein said signal supplying means comprises conductors for carryingelectrical signals from the power source to the heating elements.
 14. Asystem as in claim 12 wherein said ignition signal supplying meansfurther comprises means for receiving an externally transmitted signalfor initiating operation of the switching circuit.